Zinc Promotes Microglial Autophagy Through NLRP3 Inflammasome Inactivation via XIST/miR-374a-5p Axis in Spinal Cord Injury

Zhao, Xiaojun; Sun, Jufeng; Yuan, Yajiang; Lin, Sen; Lin, Jiaquan; Mei, Xifan

doi:10.1007/s11064-021-03441-8

Cited by 12 publications

(11 citation statements)

References 25 publications

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“…Recent literatures suggested protective role of Xist downregulation in microglia. It reported that Xist knockdown led to microglial autophagy-mediated NLRP3 inactivation in LPS-induced BV2 cells [29], which implicates a protective role of Xistmicroglial subpopulation in 5xFAD mice. For Ccl4 hi , Ifit3 + , Mcm3 + and Ccnb2 + microglia, we have found that these microglial subpopulations have already been introduced in a previous report.…”

Section: Discussionmentioning

confidence: 94%

Gossypetin ameliorates 5xFAD spatial learning and memory through enhanced phagocytosis against Aβ

Lee²,

Gon

et al. 2022

Alz Res Therapy

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Background Microglia are the resident immune cells found in our brain. They have a critical role in brain maintenance. Microglia constantly scavenge various waste materials in the brain including damaged or apoptotic neurons and Aβ. Through phagocytosis of Aβ, microglia prevent the accumulation of Aβ plaque in the brain. However, in Alzheimer’s disease (AD) patients, chronic exposure to Aβ makes microglia to become exhausted, which reduces their phagocytic activity against Aβ. Since microglia play an important role in Aβ clearance, enhancing microglial phagocytic activity against Aβ is a promising target for AD treatment. Therefore, there is a great need for therapeutic candidate that enhances microglial Aβ clearance while inhibiting microglia’s pathogenic properties. Methods In vivo studies were conducted with 5xFAD AD model mice by treating gossypetin for 13 weeks through intragastric administration. Their spatial learning and memory were evaluated through behavior tests such as Y-maze and Morris Water Maze test. Hippocampus and cortex were acquired from the sacrificed mice, and they were used for histological and biochemical analysis. Also, mouse tissues were dissociated into single cells for single-cell RNA sequencing (scRNA-seq) analysis. Transcriptome of microglial population was analyzed. Mouse primary microglia and BV2 mouse microglial cell line were cultured and treated with fluorescent recombinant Aβ to evaluate whether their phagocytic activity is affected by gossypetin. Results Gossypetin treatment improved the spatial learning and memory of 5xFAD by decreasing Aβ deposition in the hippocampus and cortex of 5xFAD. Gossypetin induced transcriptomic modulations in various microglial subpopulations, including disease-associated microglia. Gossypetin enhanced phagocytic activity of microglia while decreasing their gliosis. Gossypetin also increased MHC II+ microglial population. Conclusions Gossypetin showed protective effects against AD by enhancing microglial Aβ phagocytosis. Gossypetin appears to be a novel promising therapeutic candidate against AD.

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Section: Discussionmentioning

confidence: 94%

Gossypetin ameliorates 5xFAD spatial learning and memory through enhanced phagocytosis against Aβ

Lee²,

Gon

et al. 2022

Alz Res Therapy

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“…For example, miR-20a-5p, which is associated with CD46, is involved in autophagy-induced apoptosis and inflammation in asthma ( 43 ), but long-chain noncoding RNA can be used as “molecular sponge” of miR-20a-5p to participate in the regulation of target gene expression ( 44 ). Evidence showed that MALAT1 and XIST are involved in the process of autophagy of immune cells ( 45 ). Finally, eight potentially important small molecules targeting asthma were screened by the cMAP database, and seven of them had significant correlation with TBXA2R.…”

Section: Resultsmentioning

confidence: 99%

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment

et al. 2022

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BackgroundAutophagy has been proven to play an important role in the pathogenesis of asthma and the regulation of the airway epithelial immune microenvironment. However, a systematic analysis of the clinical importance of autophagy-related genes (ARGs) regulating the immune microenvironment in patients with asthma remains lacking.MethodsClustering based on the k-means unsupervised clustering method was performed to identify autophagy-related subtypes in asthma. ARG-related diagnostic markers in low-autophagy subtypes were screened, the infiltration of immune cells in the airway epithelium was evaluated by the CIBERSORT, and the correlation between diagnostic markers and infiltrating immune cells was analyzed. On the basis of the expression of ARGs and combined with asthma control, a risk prediction model was established and verified by experiments.ResultsA total of 66 differentially expressed ARGs and 2 subtypes were identified between mild to moderate and severe asthma. Significant differences were observed in asthma control and FEV1 reversibility between the two subtypes, and the low-autophagy subtype was closely associated with severe asthma, energy metabolism, and hormone metabolism. The autophagy gene SERPINB10 was identified as a diagnostic marker and was related to the infiltration of immune cells, such as activated mast cells and neutrophils. Combined with asthma control, a risk prediction model was constructed, the expression of five risk genes was supported by animal experiments, was established for ARGs related to the prediction model.ConclusionAutophagy plays a crucial role in the diversity and complexity of the asthma immune microenvironment and has clinical value in treatment response and prognosis.

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“…Zn also played a neuroprotective role by suppressing NLRP3 inflammasome activation through autophagy and ubiquitination in an experimental spinal cord injury model (39,83). Another study also showed that Zn suppressed NLRP3 activation by inducing microglia autophagy and played a neuroprotective role in spinal cord injury (40). Moreover, Zn participated in LPS and hypoxia inducing NLRP3 inflammasome activation in the microglia (41).…”

Section: Zincmentioning

confidence: 92%

NLRP3 inflammasome activation in response to metals

Huang

Zhang²,

Qiu³

et al. 2023

Front. Immunol.

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Implant surgery is followed by a series of inflammatory reactions that directly affect its postoperative results. The inflammasome plays a vital role in the inflammatory response by inducing pyroptosis and producing interleukin-1β, which plays a critical role in inflammation and tissue damage. Therefore, it is essential to study the activation of the inflammasome in the bone healing process after implant surgery. As metals are the primary implant materials, metal-induced local inflammatory reactions have received significant attention, and there has been more and more research on the activation of the NLRP3 (NOD-like receptor protein-3) inflammasome caused by these metals. In this review, we consolidate the basic knowledge on the NLRP3 inflammasome structures, the present knowledge on the mechanisms of NLRP3 inflammasome activation, and the studies of metal-induced NLRP3 inflammasome activation.

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Zinc Promotes Microglial Autophagy Through NLRP3 Inflammasome Inactivation via XIST/miR-374a-5p Axis in Spinal Cord Injury

Cited by 12 publications

References 25 publications

Gossypetin ameliorates 5xFAD spatial learning and memory through enhanced phagocytosis against Aβ

Gossypetin ameliorates 5xFAD spatial learning and memory through enhanced phagocytosis against Aβ

Autophagy-Related Genes Are Involved in the Progression and Prognosis of Asthma and Regulate the Immune Microenvironment

NLRP3 inflammasome activation in response to metals

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